Sodium Tetrathionate as a Cyanide Antidote

连四硫酸钠作为氰化物解毒剂

• 批准号: 9754887
• 负责人: GERRY R BOSS
• 金额: $ 68.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754887
• 关键词: Adolescent; Animal Model; Animals; Antidotes; Apnea; Blinded; Canis familiaris; Clinical Research; Contracts; Cyanides; DNA Sequence Alteration; Development Plans; Devices; Dimethyl Sulfoxide; Dose; Drug Approval; Drug Kinetics; Emergency Medical Technicians; Enzymes; Exposure to; FDA approved; Family suidae; Fire - disasters; Funding; Future; Gases; Gender; Human; Hydroxocobalamin; Hypotension; IGA Glomerulonephritis; In Vitro; Industrial Accidents; Industry; Inhalation; Injections; International; Intramuscular Injections; Intravenous; Manufacturer Name; Methods; Modeling; Mole the mammal; Mus; Neonatal; Oryctolagus cuniculus; Paper; Pathway interactions; Pharmaceutical Preparations; Phase; Poison; Poisoning; Positioning Attribute; Preparation; Randomized; Rattus; Reaction; Reagent; Regulatory Pathway; Route; Safety; Science; Sodium; Sodium Nitrite; Sulfur; Syringes; System; Terrorism; Testing; Thiocyanates; Thiosulfate Sulfurtransferase; Thromboangiitis Obliterans; Time; Toxic effect; Toxicogenetics; Vendor; Vulnerable Populations; Work; analog; animal rule; aqueous; cobinamide; commercialization; emergency service responder; in vitro Bioassay; intravenous injection; manufacturing scale-up; mass casualty; meetings; mouse model; novel therapeutics; phase 1 study; preclinical development; pregnant; product development; programs; safety study; sodium thiosulfate; stability testing

Cyanide is a rapidly acting poison, and, thus, antidotes must be administered quickly. For treating mass casualties in the field—as could occur after a major industrial accident or a terrorist attack—probably the best mode of treatment is intramuscular injection using a pre-filled syringe or autoinjector. Sodium tetrathionate (Na2S4O6) has been known for some time to be an effective cyanide antidote. It can neutralize two cyanide molecules by a direct reaction with cyanide generating thiocyanate and thiosulfate, and then by a rhodanese- dependent reaction of thiosulfate with cyanide, also generating thiocyanate. Although tetrathionate is unstable in aqueous solutions, we devised a method to stabilize tetrathionate solutions by adding low concentrations of dimethyl sulfoxide; this would allow sodium tetrathionate to be pre-loaded into syringes at the time of manufacturing. We have found that sodium tetrathionate rescues rabbits, pigs, and mice from lethal cyanide poisoning, and now propose to determine the human dose in rigorous, randomized, blinded studies in rabbits and pigs; because cyanide antidotes will be approved by the FDA via the “Animal Rule Pathway,” human doses of antidote are established in animal studies. We also propose to determine if sodium tetrathionate is effective in pregnant, neonatal, juvenile, and old animals, using mice for these studies due to the large number of animals required. The proposed project is for three years, and, during the last year, we plan to have a FDA pre-IND meeting. To that end, we will conduct FDA-required studies, including determining the pharmacokinetic and safety profile of sodium tetrathionate in two animal species—rats and dogs, and testing if tetrathionate causes genetic mutations. We will identify companies capable of large-scale synthesis of sodium tetrathionate, syringe and auto-injector manufacturers, and fill-and-finish contract organizations. For the Animal Rule Pathway, the FDA requires that the pivotal animal studies be done using the exact device that will ultimately be marketed and that stability testing be initiated in the device prior to starting Phase I clinical studies; although the pivotal animal studies and Phase I studies would be done after completion of the proposed work, we need to arrange for the injection devices at this time to allow for smooth and uninterrupted future work. We will develop a User Requirements Document for a future human factors study, a Target Product Profile suitable for FDA submission, and a detailed Product Development Plan. In addition to a pre- IND meeting during the last year, we plan to have a BARDA Tech Watch meeting, and submit a BARDA White Paper. The latter will position us to transition to BARDA funding after project completion.

氰化物是一种快速作用的毒药，因此解毒剂必须迅速服用。用于治疗肿块 在现场的伤亡-可能发生在重大工业事故或恐怖袭击后-可能是最好的 治疗方式是使用预充式注射器或自动注射器进行肌内注射。连四硫酸钠 Na 2S 4 O 6是一种有效的氰化物解毒剂。它能中和两种氰化物 分子通过与氰化物直接反应生成硫氰酸盐和硫代硫酸盐，然后通过罗丹酸- 硫代硫酸盐与氰化物的依赖性反应，也产生硫氰酸盐。虽然连四硫酸盐不稳定 在水溶液中，我们设计了一种通过加入低浓度的 二甲基亚砜;这将允许连四硫酸钠在注射时预装入注射器中。 制造业我们已经发现连四硫酸钠可以从致命的氰化物中拯救兔子、猪和老鼠 中毒，现在建议在兔子中进行严格的，随机的，盲法研究来确定人体剂量 和猪;因为氰化物解毒剂将通过“动物规则途径”获得FDA批准， 解毒剂的剂量在动物研究中确定。我们还建议确定连四硫酸钠是否 在妊娠、新生、幼年和老年动物中有效，由于大量使用小鼠进行这些研究 所需的动物。拟议的项目为期三年，在最后一年，我们计划设立一个FDA， IND前会议为此，我们将进行FDA要求的研究，包括确定 连四硫酸钠在两种动物物种-大鼠和狗中的药代动力学和安全性特征， 连四硫酸盐导致基因突变。我们将确定有能力大规模合成钠的公司 连四硫酸盐、注射器和自动注射器制造商以及灌装和成品合同组织。为 根据动物规则途径，FDA要求关键动物研究必须使用能够 最终上市，并在开始I期临床试验前启动器械稳定性试验 研究;尽管关键动物研究和I期研究将在完成 建议的工作，我们需要安排注射装置在这个时候，以允许顺利和不间断 未来的工作。我们将为未来的人为因素研究制定用户需求文档，目标 适用于FDA提交的产品简介，以及详细的产品开发计划。除了一个预- 在去年的IND会议上，我们计划举行一次巴尔达技术观察会议，并提交一份巴尔达白色 本文后者将使我们在项目完成后过渡到巴尔达资助。

项目成果

Intramuscular sodium tetrathionate as an antidote in a clinically relevant swine model of acute cyanide toxicity.

• DOI: 10.1080/15563650.2019.1602272
• 发表时间: 2020-01
• 期刊: Clinical toxicology (Philadelphia, Pa.)
• 作者: Hendry-Hofer TB;Witeof AE;Ng PC;Mahon SB;Brenner M;Boss GR;Bebarta VS
• 通讯作者: Bebarta VS

Development of sodium tetrathionate as a cyanide and methanethiol antidote.

• DOI: 10.1080/15563650.2021.1953517
• 发表时间: 2022-03
• 期刊: Clinical toxicology (Philadelphia, Pa.)
• 作者: Chan A;Lee J;Bhadra S;Bortey-Sam N;Hendry-Hofer TB;Bebarta VS;Mahon SB;Brenner M;Logue B;Pilz RB;Boss GR
• 通讯作者: Boss GR